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1.
Br J Anaesth ; 123(6): 865-876, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31591020

RESUMO

BACKGROUND: There is growing interest in the effect of postoperative analgesics on oncological outcomes after cancer surgery. We investigated the impact of tramadol after breast cancer surgery on recurrence and mortality and explored the mechanism by which tramadol affects cultured breast cancer cells in vitro. METHODS: Electronic medical records of patients who underwent breast cancer surgery between November 2005 and December 2010 at Severance Hospital in Korea were reviewed. Cox regression analyses were used to identify factors related to postoperative recurrence and mortality. We performed the sensitivity test with propensity score matching to adjust for selection bias. In addition, we investigated the effects of tramadol on human breast adenocarcinoma (Michigan Cancer Foundation-7 [MCF-7]) cells via assessment of cell viability, clonogenic assay, and cell cycle analysis in vitro. RESULTS: Of 2588 breast cancer patients, 36.4% had received tramadol. Those who received tramadol had a 0.71-fold decreased risk of recurrence and a 0.56-fold decrease in mortality. The MCF-7 cell viability assays showed that tramadol had an anti-proliferative effect by cell cycle arrest, suppressing colony formation, and regulation of oestrogen and progesterone receptors. Tramadol induced apoptosis of MCF-7 cells via extracellular signal-regulated kinases by decreasing of 5-hydroxytryptamine (HT)2B receptor and transient receptor potential vanilloid-1 expression. CONCLUSIONS: After breast cancer surgery, patients who received tramadol had a decreased risk of postoperative recurrence and mortality. The anti-tumour effect of tramadol appears to involve inhibition of proliferation, induction of apoptosis, and effects on 5-HT2B receptor and TRPV-1.


Assuntos
Adenocarcinoma/cirurgia , Analgésicos Opioides/farmacologia , Neoplasias da Mama/cirurgia , Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Tramadol/farmacologia , Adulto , Idoso , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/cirurgia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , Células MCF-7 , Mastectomia , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Células Tumorais Cultivadas
2.
Anticancer Res ; 39(8): 4031-4041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366485

RESUMO

BACKGROUND/AIM: Eribulin is currently used to treat advanced and metastatic breast cancer in the clinical setting; however, its efficacy is inhibited by resistance acquisition in many cases. Thus, the present study established two eribulin-resistant breast-cancer cell lines, and used these to investigate the mechanisms that underly eribulin-resistance acquisition. MATERIALS AND METHODS: Eribulin-resistant breast-cancer cell lines were generated by culturing MDA-MB-231 and MCF-7 cells with increasing concentrations of eribulin. RESULTS: The eribulin-resistant cells acquired resistance to eribulin, as well as several other anticancer drugs. After eribulin treatment, the eribulin-resistant cell lines showed no morphological change, no increased expression of epithelial-cadherin, nor any significant alteration in cell-cycle distribution. In contrast, the expression levels of programmed death-ligand 1 were increased in the MCF-7/eribulin-resistant compared to MCF-7 cells. CONCLUSION: The herein developed eribulin-resistant cell lines acquired cross-resistance to various anticancer agents, and displayed resistance to eribulin-induced effects on microtubule function and epithelial-mesenchymal transition (EMT).


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Furanos/administração & dosagem , Cetonas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Células MCF-7 , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 39(8): 4393-4398, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366535

RESUMO

BACKGROUND/AIM: Metastatic breast cancer (MBC) represents a wide spectrum of heterogeneous conditions with different secondary spread sites, time to relapse and biology. MBC is still considered an incurable disease despite the fact that survival rates have improved in the last years. Cutaneous metastases are a rare site for metastatic spread and indicate advanced disease. The aim of this study is to demonstrate the excellent therapeutic result following endocrine therapy only in MBC with just skin involvement. CASE REPORT: We present a case of an 82-year-old woman with no family history of breast cancer (BC), who was diagnosed with de novo metastatic estrogen/progesterone receptor-positive and HER2-negative invasive lobular BC. The only site of secondary spread was the skin. She was treated with just endocrine therapy for 116 months with which she achieved and maintained long-term complete clinical response (CR). DISCUSSION: To our knowledge this is the only case of lobular BC with de novo metastatic manifestation as multiple skin metastases, which achieved CR following the aromatase inhibitor treatment (anastrozole) with such impressive long-term overall survival.


Assuntos
Anastrozol/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Anastrozol/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/secundário
4.
BMC Endocr Disord ; 19(1): 72, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296213

RESUMO

BACKGROUND: Further knowledge about the pubertal development mode of girls with Turner syndrome (TS) who have undergone hormone replacement therapy (HRT) is beneficial to the proposal of an optimal HRT regimen. This study examined the pubertal development mode of girls with TS who underwent HRT and evaluated the characteristics of optimal sex induction therapy in girls with TS. METHOD: We conducted a retrospective, longitudinal study over the past two decades at The First Affiliated Hospital, Sun Yat-sen University. PATIENTS: Seventy-one patients with TS and two groups of normal Chinese girls. RESULTS: The total investigation time was 3.00 (2.00, 4.66) years. The interval of each stage was significantly longer (P < 0.001) in the girls with TS than that in the normal Chinese girls, except for B2-3 (P = 0.011). The uterine volumes of the girls with TS in stages B2 and 3 were greater than those of the control group (P = 0.046), whereas the uterine volume of the control group was inversely greater than that of the TS group among those who reached stages B4 and 5 (P = 0.034). During HRT, the uterine volume grew significantly from all previous stages except for breast stage 5 (B3 vs.2: Z = - 2.031; P = 0.042; B4 vs. 3: Z = - 2.273; P = 0.023; B5 vs. 4: Z = - 1.368; P = 0.171). The paired data of 27 girls with TS showed that the uterine volume (17.93 ± 9.31 ml vs. 13.75 ± 6.67 ml) and width (2.54 ± 0.66 cm vs. 2.22 ± 0.36 cm) increased significantly during artificial cycles compared with before artificial cycles (t = - 2.79 and - 2.51, P = 0.01 and 0.018). CONCLUSION: HRT led to normal breast development in girls with TS; half of the girls with TS in our study reached Tanner stage B5, although the uterus ultimately developed suboptimally. The girls' breasts and uteruses grew quickly at the beginning of HRT (stages B2-4). An optimal HRT regimen for girls with TS may specifically focus on Tanner stages B2-4 and artificial cycles.


Assuntos
Mama/crescimento & desenvolvimento , Terapia de Reposição Hormonal , Maturidade Sexual/efeitos dos fármacos , Síndrome de Turner/tratamento farmacológico , Mama/efeitos dos fármacos , China , Feminino , Humanos , Estudos Longitudinais , Análise Multivariada , Estudos Retrospectivos
5.
Mar Drugs ; 17(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349625

RESUMO

Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Monoterpenos/farmacologia , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Inibidores de Caspase/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Fase G2/efeitos dos fármacos , Histonas/metabolismo , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Plocamium/química , Rodófitas/química
6.
Life Sci ; 232: 116610, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254584

RESUMO

AIMS: The aim of this study was the characterization of the in vitro cytotoxic properties of a recently isolated diterpene compound, 7ß-acetoxy-20-hydroxy-19,20-epoxyroyleanone (compound 1), extracted from Salvia corrugata, versus human cell lines. MAIN METHODS: We used as model study immortalized breast epithelial cells MCF10A and two ERBB2+ breast cancer (BCa) cell lines, SKBR-3 and BT474. Compound 1 was isolated by methanolic extraction from regenerated shoots of Salvia corrugata Vahl, and purified by high pressure liquid chromatography (HPLC). Flow cytometry (FCM) was employed for cell cycle, apoptosis and reactive oxygen species (ROS) analysis. Cell morphology was assessed by immunofluorescence and transmission electron microscopy (TEM). KEY FINDINGS: Compound 1 inhibited cell survival of all breast cell lines. In particular, compound 1 promoted cell cycle arrest in the G0/G1 phase and apoptosis along with impairment of the mitochondrial function, which was reflected in a gross alteration of the mitochondrial network structure. Furthermore, we also detected a potent activation of the ERK1/2 kinase, which suggested the induction of reactive oxygen species (ROS). Partial rescue of survival obtained with n-acetylcysteine (NAC) when coadminstered with compound 1 further supported a contribution of ROS mediated mechanisms to the growth-arrest and proapoptotic activity of compound 1 in both BCa cell lines. ROS production was indeed confirmed in SKBR-3. SIGNIFICANCE: Our findings show that compound 1 has a cytotoxic activity against both human normal and cancer cell lines derived from breast epithelia, which is mediated by ROS generation and mitochondrial damage.


Assuntos
Mama/efeitos dos fármacos , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Células Epiteliais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Mama/citologia , Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/isolamento & purificação , Células Epiteliais/metabolismo , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
7.
J BUON ; 24(2): 555-559, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128005

RESUMO

PURPOSE: The purpose of the present study was to explore the value of real-time tissue elastography (RTE) in predicting the efficacy of neoadjuvant chemotherapy (NAC) in breast cancer. METHODS: A total of 60 patients with breast cancer who received NAC in our hospital were evaluated. According to the pathological results, 47 patients were included in the significant response group and 13 patients in the non-significant response group. The maximum diameter and strain ratio (B/A ratio) of lesions before and 1st, 2nd, 4th and 6th week after NAC were recorded and compared. The RECEIVER OPERATION CHARACTERISTIC (ROC) curve of the lesion diameter and strain rate ratio (B/A value) were used to predict the value of NAC efficacy. RESULTS: The lesions in the two groups showed a honeycomb-like reduction after NAC. The blue color in the elastic image gradually decreased, and the green color gradually increased. Repeated measurement ANALYSIS OF VARIANCE (ANOVA) found that the maximum diameter and B/A value showed a downward trend within 6 weeks of NAC treatment. The maximum diameter and B/A value in the significant response group were significantly lower than the non-significant response group before and after the NAC. There was an interaction in the maximum diameter and B/A value between the significant response group and the non-significant response group. The above differences were statistically significant (all p<0.05). The AREA UNDER CURVE (AUC) of △B/A value at 2nd week of NAC was maximal (0.944), and the best diagnostic point was 5.64. The sensitivity was 92.31% and the specificity 87.23%. CONCLUSION: △B/A value at 2nd week of NAC is helpful in predicting the therapeutic effect of NAC in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Mama/diagnóstico por imagem , Técnicas de Imagem por Elasticidade , Terapia Neoadjuvante , Adulto , Mama/efeitos dos fármacos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico
8.
Integr Cancer Ther ; 18: 1534735419848047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056957

RESUMO

BACKGROUND: The tumor cells responsible for metastasis are highly resistant to chemotherapy and have characteristics of stem cells, with a high capacity for self-regeneration and the use of detoxifying mechanisms that participate in drug resistance. In vivo models of highly resistant cells allow us to evaluate the real impact of the immune response in the control of cancer. MATERIALS AND METHODS: A tumor population derived from the 4T1 breast cancer cell line that was stable in vitro and highly aggressive in vivo was obtained, characterized, and determined to exhibit cancer stem cell (CSC) phenotypes (CD44+, CD24+, ALDH+, Oct4+, Nanog+, Sox2+, and high self-renewal capacity). Orthotopic transplantation of these cells allowed us to evaluate their in vivo susceptibility to chemo and immune responses induced after vaccination. RESULTS: The immune response induced after vaccination with tumor cells treated with doxorubicin decreased the formation of tumors and macrometastasis in this model, which allowed us to confirm the immune response relevance in the control of highly chemotherapy-resistant ALDH+ CSCs in an aggressive tumor model in immunocompetent animals. CONCLUSIONS: The antitumor immune response was the main element capable of controlling tumor progression as well as metastasis in a highly chemotherapy-resistant aggressive breast cancer model.


Assuntos
Neoplasias da Mama/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Hospedeiro Imunocomprometido/imunologia , Animais , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/imunologia
9.
Exp Mol Pathol ; 108: 150-155, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026440

RESUMO

OBJECTIVE: To identify the relationship between clinical pathological characteristics and the recurrence score (RS) on a 21-gene expression assay in patients with hormone receptor-positive, node-negative breast cancer, as well as the effect of RS on adjuvant decision-making. METHODS: The retrospective study was conducted among luminal breast cancer patients admitted to Xijing Hospital between October 10, 2016, and September 14, 2018. Real-time PCR was used for 21-genome detection. Based on the calculated RS, participants were classified into low-risk, moderate-risk, and high-risk groups. Single-factor analysis and multiple logistic regression analysis were performed to explore independent predictors of high RS. Moreover, the effect of RS on adjuvant decision-making was studied. RESULTS: Two hundred twenty-two patients with luminal breast cancer, aged 48.3 ±â€¯9.66, were enrolled. Among them, 33.8% had low (13 ±â€¯3.34), 45.5% intermediate (23 ±â€¯3.65), and 20.7% high (37 ±â€¯3.44) RS. According to the single-factor analysis, age, tumor size, Ki-67, molecular subtype, CK5/6 expression, E-cadherin level, and histological grade were positively associated with high RS. Multiple logistic analyses showed that tumor size and histological grade were independent variables that might predict high RS in patients with hormone receptor-positive, node-negative breast cancer. For adjuvant decision-making, the proportion of adjuvant chemotherapy in the intermediate-/high-risk groups was higher than that in the low-risk group, P < 0.001. Compared with the data worldwide, the changes of treatment selection in the present study were similar to those in Japan (23.0% vs. 26%) and America (23.0% vs. 23.0%). Considering the pathology types, 14.3% of patients with invasive breast cancer with lower RS changed treatment recommendations, predominantly from chemo-endocrine to endocrine treatment alone, whereas the percentage in intermediate/high RS groups was 8.1%. CONCLUSIONS: Tumor size and histological grade were independent variables, predicting high risk in patients with hormone receptor-positive, node-negative breast cancer; 21-gene RS assessment was potentially a critical tool in guiding adjuvant decision-making in China.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/genética , Receptores Estrogênicos/metabolismo , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Quimioterapia Adjuvante , China , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco
10.
ACS Appl Mater Interfaces ; 11(18): 16347-16356, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31032616

RESUMO

We report new surface coatings that adhesively distinguish three breast epithelial cell lines (MCF-10A, MCF-7, and TMX2-28) when cell suspensions in buffer or breast milk are flowed over the coatings. We also report the selective capture of epithelial cells and rejection of Jurkat lymphocytes, with average selectivities exceeding 60 and captured cell purities often exceeding >99%. The surfaces achieve the dual goals of selective cell capture and resistance to fouling by proteins and other components of breast milk. The coatings do not rely on antibody targeting of cell surface markers but instead contain polycation chains embedded within a layer of end-tethered poly(ethylene glycol) (PEG) chains. The PEG, somewhat shielding the polycations, prevents surface fouling by proteins, nondesired cells, and other milk components, while the polycations produce electrostatic attractions that are heterogeneous on nanoscopic length scales. These electrostatic heterogeneities on the engineered coating, shown to produce curvature-selective particle capture in other studies, produce cell selectivity here. The ability of the engineered surfaces to discriminate these cell lines via an electrostatic driving force is remarkable, as the cells are of very similar surface charge as evidenced by their nearly identical ζ-potentials. The current surfaces, which likely distinguish cells based on their electrostatic surface landscape combined with other factors, adhesively distinguish cell lines that may differ only slightly in their expression of a surface marker, or cancer cells that minimally express EpCAM but which have different distributions of electrostatic charge on their surfaces. These surfaces are among the first to be documented for the compatibility of a polymer brush with human breast milk and may find use in technologies that capture cells from human breast milk or other complex fluids for cancer risk assessment.


Assuntos
Adesivos/farmacologia , Mama/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Leite Humano/química , Adesivos/química , Mama/citologia , Tampões (Química) , Molécula de Adesão da Célula Epitelial/genética , Células Epiteliais/química , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Células Jurkat , Células MCF-7 , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Propriedades de Superfície
11.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30871042

RESUMO

The anthracycline antibiotic doxorubicin is commonly used antineoplastic drug in breast cancer treatment. Like most chemotherapy, doxorubicin does not selectively target tumorigenic cells with high proliferation rate and often causes serve side effects. In the present study, we demonstrated the cellular senescence and senescence associated secretory phenotype (SASP) of both breast tumor cell MDA-MB-231 and normal epithelial cell MCF-10A induced by clinical dose of doxorubicin (100 nM). Senescence was confirmed by flattened morphology, increased level of beta galactose, accumulating contents of lysosome and mitochondrial, and elevated expression of p16 and p21 proteins. Similarly, SASP was identified by highly secreted proteins IL-6, IL-8, GRO, GM-CSF, MCP-1, and MMP1 by antibody array assay. Reciprocal experiments, determined by cell proliferation and apoptosis assays and cell migration and cell invasion, indicated that SASP of MDA-MB-231 cell induces growth arrest of MCF-10A, whereas SASP of MCF-10A significantly stimulates the proliferation of MDA-MB-231. Interestingly, SASP from both cells powerfully promotes the cell migration and cell invasion of MDA-MB-231 cells. Treatment with the natural product ginsenoside Rh2 does not prevent cellular senescence or exert senolytic. However, SASP from senescent cells treated with Rh2 greatly attenuated the above-mentioned bystander effect. Altogether, Rh2 is a potential candidate to ameliorate this unwanted chemotherapy-induced senescence bystander effect.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Efeito Espectador/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Células Epiteliais/efeitos dos fármacos , Ginsenosídeos/farmacologia , Apoptose/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Invasividade Neoplásica/patologia
12.
Surgery ; 165(5): 1008-1013, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30777364

RESUMO

BACKGROUND: Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease. METHODS: A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA. RESULTS: Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f±, CD24± expression were present in chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in chemotherapy-naïve specimens versus residual disease specimens in both patient-paired and unpaired breast cancers. CONCLUSION: Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naïve breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/terapia , Mama/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mama/efeitos dos fármacos , Mama/cirurgia , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante/métodos , Neoplasia Residual , Células-Tronco Neoplásicas/metabolismo , Resultado do Tratamento
13.
Breast Cancer Res Treat ; 175(2): 379-387, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30759288

RESUMO

BACKGROUND: Invasive lobular carcinomas (ILCs) represent approximately 10% of all breast cancers. Despite this high frequency, benefit of adjuvant chemotherapy (CT) is still unclear. METHODS: Our objective was to investigate the impact of CT on survival in ILC. Patients were retrospectively identified from a cohort of 23,319 patients who underwent primary surgery in 15 French centers between 1990 and 2014. Only ILC, hormone-positive, human epidermal growth factor 2 (HER2)-negative patients who received adjuvant endocrine therapy (ET) were included. End-points were disease-free survival (DFS) and overall survival (OS). A propensity score for receiving CT, aiming to compensate for baseline characteristics, was used. RESULTS: Of a total of 2318 patients with ILC, 1485 patients (64%) received ET alone and 823 (36%) received ET + CT. We observed a beneficial effect of addition of CT to ET on DFS and OS in multivariate Cox model (HR = 0.61, 95% confidence interval, CI [0.41-0.90]; p = 0.01 and 0.52, 95% CI [0.31-0.87]; p = 0.01, respectively). This effect was even more pronounced when propensity score matching was used. Regarding subgroup analysis, low-risk patients without CT did not have significant differences in DFS or OS compared to low-risk patients with CT. CONCLUSION: ILC patients could derive significant DFS and OS benefits from CT, especially for high-risk patients.


Assuntos
Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Quimioterapia Adjuvante , Adulto , Idoso , Mama/efeitos dos fármacos , Mama/patologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Fatores de Risco , Resultado do Tratamento
14.
Breast Cancer Res ; 21(1): 24, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760301

RESUMO

BACKGROUND: Breast density is strongly related to breast cancer. Identifying associations between environmental exposures and density may elucidate relationships with breast cancer. Metals and polycyclic aromatic hydrocarbons (PAHs) may influence breast density via oxidative stress or endocrine disruption. METHODS: Study participants (n = 222,581) underwent a screening mammogram in 2011 at a radiology facility in the Breast Cancer Surveillance Consortium. Zip code residential levels of airborne PAHs and metals (arsenic, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, and selenium) were assessed using the 2011 EPA National Air Toxics Assessment. Breast density was measured using the Breast Imaging-Reporting and Data System (BI-RADS) lexicon. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the individual air toxics and dense breasts (BI-RADS 3 or 4). Weighted quantile sum (WQS) regression was used to model the association between the air toxic mixture and density. RESULTS: Higher residential levels of arsenic, cobalt, lead, manganese, nickel, or PAHs were individually associated with breast density. Comparing the highest to the lowest quartile, higher odds of having dense breasts were observed for cobalt (OR = 1.60, 95% CI 1.56-1.64) and lead (OR = 1.56, 95% CI 1.52-1.64). Associations were stronger for premenopausal women. The WQS index was associated with density overall (OR = 1.22, 95% CI 1.20-1.24); the most heavily weighted air toxics were lead and cobalt. CONCLUSIONS: In this first study to evaluate the association between air toxics and breast density, women living in areas with higher concentrations of lead and cobalt were more likely to have dense breasts.


Assuntos
Poluentes Atmosféricos/toxicidade , Densidade da Mama/efeitos dos fármacos , Metais/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Adulto , Idoso , Mama/diagnóstico por imagem , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Estudos Transversais , Detecção Precoce de Câncer/métodos , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Sistema de Registros/estatística & dados numéricos
15.
Cancer Lett ; 447: 24-32, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30684594

RESUMO

Breast tumor metastasis is a leading cause of cancer-related deaths worldwide. Breast cancer (BC) cells frequently metastasize to the lungs, where they pose a formidable therapeutic challenge. In the current study, we evaluated the anti-proliferative and anti-metastatic effects of 2'-hydroxyflavanone (2HF) and RLIP inhibition in an array of triple-negative BC cell lines and an orthotopic mouse model of breast-to-lung metastasis. Compared to control treatment, RLIP inhibition reduced in-vitro cell viability and suppressed the migratory and invasive potential of BC cells. In-vitro studies showed that 2HF treatment reduced the expression of RLIP, KRAS, pERK, pSTAT3, and pP70S6K. Further, mice orthotopically implanted with lung-seeking luciferase-expressing TMD231 cells were treated with 2HF (50 mg/kg, b.w.), RLIP antisense (RAS; 5 mg/kg, b.w.), RLIP antibody (Rab; 5 mg/kg, b.w.) or a combination of 2HF + RAS + Rab. 2HF-, RAS-, and Rab-treated mice exhibited significantly lower primary tumor weight and reduced lung metastasis compared to control mice. Mice treated with a combination of 2HF + RAS + Rab exhibited no metastasis and significantly lower tumor weight than the single agent-treated mice. Collectively, our results suggest that 2HF has potential to be combined with RLIP inhibition/depletion to more effectively suppress primary breast tumor growth and metastasis to the lungs.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Flavanonas/farmacologia , Proteínas Ativadoras de GTPase/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Animais , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Mol Cancer ; 18(1): 9, 2019 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-30636640

RESUMO

BACKGROUND: Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression. METHODS: We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels. RESULTS: We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer. CONCLUSIONS: These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , RNA Interferente Pequeno/genética , Selenoproteína W/genética , Animais , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , MicroRNAs/genética , Paclitaxel/farmacologia , Prognóstico , Pseudogenes , RNA Mensageiro/genética , RNA Interferente Pequeno/biossíntese , Regulação para Cima
17.
Biochem Biophys Res Commun ; 509(2): 476-482, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30595381

RESUMO

Dysregulation of steroid biosynthesis has been implicated in the pathophysiology of a variety of cancers. One such common malignancy in women is breast cancer that is frequently promoted by estrogen overproduction. All steroid hormones are made from cholesterol, and the rate-limiting step in steroid biosynthesis is primarily mediated by the steroidogenic acute regulatory (StAR) protein. Whereas the involvement of StAR in the regulation steroid hormone biosynthesis is well established, its association to breast cancer remains obscure. Herein, we report that estrogen receptor positive breast cancer cell lines (MCF7, MDA-MB-361, and T-47D) displayed aberrant high expression of the StAR protein, concomitant with 17ß-estradiol (E2) synthesis, when compared their levels with normal mammary epithelial (MCF10A and MCF12F) and triple negative breast cancer (MDA-MB-468, MDA-MB-231, and BT-549) cells. StAR was identified as a novel acetylated protein in MCF7 cells, in which liquid chromatography-tandem mass spectrometry analysis identified seven StAR acetyl lysine residues under basal and in response to histone deacetylase (HDAC) inhibition. A number of HDAC inhibitors were capable of diminishing StAR expression and E2 synthesis in MCF7 cells. The validity of StAR protein acetylation and its correlation to HDAC inhibition mediated steroid synthesis was demonstrated in adrenocortical tumor H295R cells. These findings provide novel insights that StAR protein is abundantly expressed in the most prevalent hormone sensitive breast cancer subtype, wherein inhibition of HDACs altered StAR acetylation patterns and decreased E2 levels, which may have important therapeutic implications in the prevention and treatment of this devastating disease.


Assuntos
Neoplasias da Mama/patologia , Fosfoproteínas/análise , Acetilação/efeitos dos fármacos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Estrogênios/análise , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células MCF-7 , Regulação para Cima/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 116(4): 1370-1377, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30622177

RESUMO

Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2-/-[Formula: see text] mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2-/-[Formula: see text] mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Anticorpos Monoclonais , Mama/efeitos dos fármacos , Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Células NIH 3T3 , Proteínas Nucleares/metabolismo , Paclitaxel/farmacologia , Complexo Repressor Polycomb 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo
19.
Breast Dis ; 38(1): 31-33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30530952

RESUMO

Mondor's disease can be a challenging diagnosis. The case we present is of a 29 year-old Brazilian woman, under combined hormonal contraception, who consulted for a painful lump on her right breast. She presented a complete resolution after a local treatment of heparinoid cream and a non-steroidal anti-inflammatory oral treatment, but relapsed 18 months later. Oral combined hormonal contraception was the only "risk factor" found, in this case, and the modification of the latter helped resolve the relapse clinical symptoms.


Assuntos
Doenças Mamárias/diagnóstico , Mama/efeitos dos fármacos , Anticoncepcionais Orais Hormonais/efeitos adversos , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Mamárias/diagnóstico por imagem , Doenças Mamárias/tratamento farmacológico , Feminino , Humanos , Recidiva , Fatores de Risco , Tromboflebite/diagnóstico , Resultado do Tratamento , Ultrassonografia
20.
Ann Nucl Med ; 33(3): 193-200, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30569442

RESUMO

OBJECTIVE: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor recently approved for treatment in advanced or metastatic breast cancer (BC) patients. The use of 18F-FDG PET/CT for chemo/endocrine therapy response assessment in BC patients is well reported in the literature, but no studies have evaluated its role for assessing Palbociclib efficacy in clinical practice. Our study aimed to evaluate the potential role of 18F-FDG PET/CT in this setting. METHODS: In 12 metastatic BC patients (mean age = 62 ± 10 years) treated with Palbociclib plus endocrine therapy and who underwent a baseline and post-therapy 18F-FDG PET/CT, we retrospectively compared the Metabolic Response Evaluation (MRE, based on PET/CT) to the Standard Response Evaluation (SRE, based on clinico-laboratory and morphological data); we also assessed the influence of additional PET/CT information on the patients' management. RESULTS: Compared to SRE, MRE increased the proportion of patients classified with progressive disease from 25 to 50% and differed from SRE in 8/12 patients: 3/8 shifted from stable disease or undetermined response to metabolic progression (more unfavorable category), 4/8 from stable disease to partial or complete metabolic response, and 1/8 from partial response to complete metabolic response (more favorable category). Additional PET/CT information led to a change in patients' management in 3/12 (25%) patients. CONCLUSION: In BC patients treated with Palbociclib, additional 18F-FDG PET/CT information seems clinically useful, with respect to personalized management, to early intercept patients who should discontinue Palbociclib because of progressive disease and to select patients requiring a strict monitoring of additional metabolic findings. Further studies are needed to confirm these preliminary results.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fluordesoxiglucose F18 , Piperazinas/uso terapêutico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Piridinas/uso terapêutico , Compostos Radiofarmacêuticos , Idoso , Idoso de 80 Anos ou mais , Mama/diagnóstico por imagem , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Dados Preliminares , Estudos Retrospectivos , Resultado do Tratamento , Imagem Corporal Total
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